DESCRIPTION: (Applicant's Abstract) Many abused drugs signal through the G protein pathway. All of the known opioid receptors are Gi coupled. The role of Gi in drug addiction will be explored using a novel system that provides direct control of Gi signaling in vivo, with temporal, spatial and pharmacological specificity. Genetically modified Gi-coupled kappa-opioid receptors can be activated only by the synthetic ligand spiradoline, and not by endogenous ligands. Inducible expression of this Receptor Activated Solely by Synthetic Ligand (RASSL) in selected brain regions of transgenic mice will be used to assess the functional consequences of Gi stimulation in those regions. Specific Aim 1: To gain control of Gi signaling in brain regions that contribute to the development of addiction. The kappa-opioid RASSL has been placed under the control of the tetracycline-controlled, inducible, tissue-specific expression system. This allows the RASSL to be expressed specifically in neural reward regions and activated by an exogenous drug, spiradoline, at precise times. Specific Aim 2: To characterize which specific behaviors associated with addiction, such as drug-seeking, drug taking, or withdrawal, are mediated by Gi signaling. Stimulation of the RASSL in neural reward regions should evoke some of the behaviors associated with addiction. Techniques to assess the behavioral response to RASSL stimulation will include drug, self-administration, conditioned place preference, and evaluation of withdrawal symptoms.